NLR in host response to y-herpesviruses The Nod-like Receptor (NLR) family represents intracellular sensors important in initiating innate immunity. NLRs activate several classes of innate immune response proteins, including inflammatory Caspases involved in cytokine processing and apoptosis, components of the IKB Kinase (IKK) complex responsible for NF-KB induction, and the MAVS-dependent pathway for activating IRF family transcription factors that induce Interferons. Cytosolic viral DNA activates NLRs, defining an innate immunity mechanism for initiating host responses to infectious DNA viruses. The y-herpesviruses such as Human Herpesvirus 8 (HHV8) (the agent responsible for Kaposi Sarcoma) and its mouse counterpart MHV-68 are DNA viruses whose pathobiology includes both lytic and latent types of infection. It remains unclear how these viruses thwart host defense mechanisms to propagate their genomes through cycles of acute infection and reactivation from latent infection. In this Project, the hypothesis will be tested that y-herpesviruses HHV8 and MHV68 suppress innate immune responses by modulating NLRs. Preliminary data are presented that demonstrate (a) suppression of MHV-68 viral gene expression by NLRs; (b) discovery of viral gene products that interact with NLRs; and (c) effects of y-herpesviruses on expression of cellular microRNAs (miRs) that modulate NLR activity in infected cells. Our proposed Specific Aims are to: (1) Explore the effects of NLRs on y-herpesvirus viral replication and viral gene expression; (2) Determine the MHV-68 and HHVB viral gene products that interact with inflammasome components, assessing the functional significance of these protein interactions for viral replication and pathogenesis; (3) Elucidate the molecular mechanisms by which NLR-interacting viral gene products and virus-regulated miRs modulate NLR activity; and (4) Determine the impact of viral gene products (proteins and miRs) that regulate NLRs on immune responses to y-herpesviruses and apply findings towards vaccine strategies. The studies will provide insights into the roles of NLR-family proteins in host defense against y-herpesviruses, and aid development of vaccine strategies